Transdermal compositions with enhanced skin penetration properties

ABSTRACT

The invention relates to a transdermal therapeutic system for application to the skin and/or mucosa consisting of at least one active substance in the form of a solid dispersion in combination with at least one destructuring agent and/or at least one structuring agent in a common matrix.

This application is a 371 of PCT/DE98/00157 filed Jan. 13, 1998.

DESCRIPTION

The invention relates to a transdermal therapeutic system forapplication to the skin and/or mucosa consisting of at least one activesubstance in the form of a solid dispersion in combination with at leastone destructuring agent and/or at least one structuring agent in acommon matrix.

The invention thus relates to a method for improving the cutaneouspermeation of active substances, which can be employed in particular forproducing a transdermal therapeutic system (TTS) intended forapplication to the skin or mucosa.

The term “TTS” describes an administration device which adheres to thetarget organ which is the skin or mucosa and moreover allows thecontained medicinal substance to exert systemic activity in the body bypassing through the target organ.

The terms destructuring agent and structuring agent derive from the“ice” theory of hydrogels as described, for example, by Hüttenrauch etal. (Pharmazie 40, p. 427, 1985).

Compositions used for transdermal administration of active substancesare known in a wide variety of forms:

U.S. Pat. No. 4,777,047 describes formulations for transdermaladministration which contain a calcium channel blocker andsurface-active auxiliaries such as isopropyl myristate or ethyl oleatein a solvent. The solvents generally mentioned are propylene glycol,linolenic acid, oleyl alcohol, Solketal or dimethyl sulphoxide.

U.S. Pat. No. 5,422,361 describes a cream or lotion which contains alipophilic pharmaceutical active substance. The basic material used inthis case is a physically and chemically stable oil-in-water emulsionwhich has a content of N-methyl-2-pyrrolidone, dimethyl sulphoxide,Solketal or oleyl alcohol. The basic materials described for Solketaland dimethyl sulphoxide have a maximum content of these substances of10% by weight.

DE-C 43 09 830 describes an active substance plaster for deliveringestradiol to the skin. The active substance plaster has an activesubstance reservoir consisting of a contact adhesive. A penetrationaccelerant, namely monoisopropylideneglycerol (MIPG, Solketal) ormonoisopropylidenediglycerol (MIPD) is present in the polymer matrix ofthe contact adhesive to improve the bioavailability of estradiol.

Akhter, S. A. et al. (J. Pharm. Pharmacol. 36, Suppl., p. 7 (1984))describe solutions of an active substance in the solvent Solketal towhich 7% oleic acid is added as penetration-enhancing agent.

Dosage forms of these types for transdermal administration may beadequate for certain purposes, in particular for active substances forwhich the permeability of the skin is relatively good. However, as arule, the epidermis, for example of humans, has relatively lowpermeability for active substances. Accordingly, on use of the knownformulations, ordinarily too little active substance is transportedthrough the skin into the bloodstream. In addition, cutaneousintolerance is common, such as, for example, skin irritation or evenallergic effects. This is particularly true when steroid hormones are tobe employed as active substances.

The preferred area of use of transdermal medicinal forms are symptoms,diseases, deficiency states and similar needs, such as nausea,heart/circulatory failure, hormone deficiency, the wish forcontraception. These needs require provision of the active substancewhich is longer lasting, uniform or adapted to the biological rhythm ofthe blood level.

Typical TTSs release the contained medicinal substance uniformly over aprolonged period. However, additionally more complicated systems andmixed types (mixed systems) have also been described. Examples of TTSsmentioned by D'Mello (Transdermal Patch Drug Delivery, Scrip reportBS750, PJB Publications Ltd., 1995) or in the “Rote Liste” (publisher:Bundesverband der pharmazeutischen Industrie (BPI), 1996) are:

Nicotine patches,

Hyoscine patch,

Glyceryl trinitrate patches,

NSAID patches,

Fentanyl patch,

Clonidine patch,

Oestradiol patch,

Oestradiol/Norethisterone patch,

Estradiol vaginal rings,

Isosorbide dinitrate ointments,

Isosorbide dinitrate transdermal sprays,

Glyceryl trinitrate ointments.

TTSs for insulin and other peptide active substances, including certain“releasing hormones”, are being developed.

The production of the TTSs disclosed to date already in many cases takesaccount of the fact that not all active substances permeate through theskin to a sufficient extent. However, satisfactory functioning of thesystems depends crucially on ensured permeation.

According to the recent review (Ghosh T. K., Banga, A. K., Pharm.Technol., 17 (March) 72-96 (1993) and 17 (April) 62-87 (1993)), thereare physical, chemical and biological possibilities for improvingcutaneous permeation. The use of so-called penetration promoters is tobe regarded as a chemical possibility. These substances penetrate intothe skin and interact with the constituents of the stratum corneum,which is the main impediment to penetration of the active substance.Penetration promoters reduce the resistance of the skin and thusincrease the passage (flux) of the active substance through the skin. Inmost cases they also beneficially affect the active substance partitionratio between skin and vehicle (Franz, T. J., Tojo, K., Shah, K. R.,Kydonieus, A., Transdermal Delivery, in Kydonieus, A. (Ed.) Treatise onControlled Drug Delivery, Marcel Dekker, Inc., 341-422 (1992); Loth, H.,Meth. and Find. Exp. Clin. Pharmacol., 11 (3), 155-164, (1989); Robson,D. L., Thesis, University of Bradford, Postgraduate School of Studies inPharmacy, 1988, p. 1-25).

The transdermal flux takes place mainly intercellularly. This involvesthe permeating substance penetrating through the lipophilic cellstructures (lipophilic route) so that penetration promoters which affectthis route ought, depending on the region of the cell structure (cf.Fartasch, M. The nature of the epidermal barrier: Structural aspects.Advan. Drug Delivery Rev. 18(3), 273-282 (1996)), to have three sites ofaction (Barry, B. W., J. Controlled Release, 15, 237-248, (1991)),namely

in the direct vicinity of polar head groups (region A)

in the aqueous region between the head groups (region B) and

within the nonpolar constituents of the lipid bilayers (region C).

The site of action of most permeation promoters is known, but detailsare still lacking for some substances (Table 1).

TABLE 1 Classification of penetration promoters according to the site ofaction Site of action (predominant) Penetration promoter Region A Water,dioxolane derivatives, ethyl acetate, urea*, ethanol and short-chainmonohydric alcohols (C₂-C₆)*, propylene glycol* Region B Ethanol RegionC DMSO*, DMF**, laurocapram and derivatives, fatty acids (e.g. oleicacid), surfactants (e.g. decyl methyl sulphoxide), terpenes UnclearIsopropanol, glycerol, monohydric alcohols assignment (C₈-C₁₄), alkanes,alkyl halides, amides, pyrrolidone derivatives, fatty acid esters,cyclodextrins, polyethylene glycols Additionally affects: *keratinfibrils **region A (solvation)

The overview in Table 1 makes it very clear that regions A and C arealmost exclusively the sites of action of the well-known permeationpromoters. These promoters aim at affecting either the head groups orthe lipophilic chains. Only ethanol is thought to act in the aqueousregion in the vicinity of the head groups. It can thus be said that thewell-known permeation promoters, with the exception of ethanol, affectin particular the lipophilic regions and promote the lipophilic flux.

On the other hand, it is known that an alteration in the lipophilicregions is associated with serious impairments of the condition of theskin. These impairments extend from drying out and embrittlement tocracks, marked irritation, reddening, exzema and similar skin damage.This also applies to ethanol, the concentration of which is thereforelimited on dermal application. In addition, ethanol has the disadvantageof ease of evaporation so that supersaturation states occur, thedisadvantages of which will be explained later.

It is, however, known that the flux is possible by two routes, by thenonpolar route already mentioned and also by the pore diffusion route(polar route) (Yamashita, F., Bando, H., Koyama, Y., Kitagawa, S.,Takakura, Y., Hashida, M., In Vivo and In Vitro Analysis of SkinPenetration Enhancement Based on a Two-layer Diffusion Model with Polarand Nonpolar Routes in the Stratum Corneum, Pharm. Res. 11, 185-191(1994)).

The total of the two fluxes is obtained as in Equation 1:

J=J _(L) +J _(P)  (Eq. 1)

with J total flux, J_(L) lipophilic flux, J_(P) pore flux

The lipophilic flux.is generally predominant. The skin is thereforescarcely permeable, in particular to hydrophilic medicinal substances,especially since the proportion of area of the pores available for thepore flux, and the size of the pores (0.38-1.58 nm) are comparativelysmall.

To improve the pore flux, it has already been proposed (Hatanaka, T.,Manabe, E., Sugibayashi, K., Morimoto, Y., An Application of theHydrodynamic Pore Theory to Percutaneous Absorption of Drugs, Pharm.Res. 11, 654-658 (1994)), to use a solvent with high cutaneouspermeability. The authors postulate that it is possible in this way totransfer active substances dissolved in the solvent through the skin. Itemerged with the example of ANP and isosorbide dinitrate (ISDN) asactive substance that the method fails with this medicinal substancewhich diffuses mainly by the lipophilic route.

The methods known to date for producing a transdermal medicinal formthus predominantly exhibit the considerable disadvantage that particularactive substances with a certain degree of hydrophilicity, for examplecertain hormones, can be transported through the skin to an onlyinadequate extent. This fact is manifested, for example, by atestosterone plaster which must be applied to the scrotum if the hormoneis to be absorbed transdermally to a sufficient extent. The proposedmethod for improving the pore flux with suitable solvents in the variantpublished by Hatanaka, T., Manabe, E., Sugibayashi, K., Morimoto, Y.appears promising, but only relatively low fluxes are achieved, and ithas yet to be proved whether active substances in fact follow thesolvent flux. In the case of ISDN, the method failed because thesubstance on its own permeates better through the skin by a factor of 10than does the ANP employed as accelerant.

U.S. Pat. No. 4,379,454 describes a dependence of the active substanceflux (estradiol) on the enhancer flux (ethanol). It was found in thiscase that an increased ethanol permeation rate likewise increases theestradiol permeation. However, there is a disadvantage in the potentialof ethanol to irritate the layers of the skin on prolonged use.

It is therefore an object of the present invention to provide a TTSwhich overcomes the abovementioned disadvantages of the state of theart.

It is therefore an object of the invention to provide compositions fortransdermal administration which are improved by comparison with knowncompositions, in particular in relation to the ability of certain activesubstances such as, for example, steroidal agents or sex hormones topenetrate. It is further intended to avoid as far as possibledisadvantages occurring, in particular skin irritation, on use of theknown preparations, whether in the form of a transdermal therapeuticsystem (TTS), of a cream, or of a lotion.

The object is achieved according to the invention by producing atransdermal therapeutic system for application to the skin and/ormucosa, consisting of at least one active substance in the form of asolid dispersion in combination with at least one destructuring agentand/or at least one structuring agent in a common matrix.

The transdermal therapeutic system according to the invention ispreferably characterized in that the solid dispersion is a moleculardispersion of the active substance in an inert carrier substance.

The inert carrier substance is selected according to the invention frominert carriers known per se for solid dispersions, such as, for example,sucrose, lactose, succinic acid, polyethylene glycols,polyvinylpyrrolidone, urea, mannitol, mannitose or mixtures thereof.

The destructuring agent is selected according to the invention from thegroup of carboxamides such as, for example, urea, nicotinamide,succinamide, methylacetamide, ethylacetamide or mixtures thereof.

The relaxation time for the transdermal therapeutic system according tothe invention is preferably more than 120 ms, by preference more than150 ms.

The structuring agent is selected according to the invention from thegroup of polyols such as, for example, glycerol, ethylene glycol,propylene glycol, from the group of sugar alcohols such as, for example,sorbitol and/or from the group of sugars such as, for example, sucroseor glucose or mixtures thereof.

The relaxation time in this case is preferably less than 119 ms, bypreference less than 80 ms.

An appropriate ratio of the components (destructuring agent/structuringagent) has proved particularly advantageous for more efficienttransdermal release.

The ratio between destructuring agent and structuring agent according tothe invention is from 10:1 to 1:10, the ratio between destructuringagent and structuring agent preferably being from 2:1 to 1:2.

The destructuring agent used is a substance which destroys the structureof water to result in a relaxation time >120 ms, preferably >150 ms.This longer relaxation time is a manifestation of a greater mobility offree water, which is thus available for solution and diffusionprocesses.

The structuring agent used is a substance which strengthens thestructure of water to result in a relaxation time <120 ms, preferably<80 ms. This shorter relaxation time is a manifestation of a reducedmobility of free water, which is thus no longer available for dissolvingand diffusion processes.

The stated facts are made clear by an investigation of the T₂ relaxationtimes for selected destructuring agents and structuring agents (Table2).

TABLE 2 T_(2 relaxation times for selected destructuring agents and)structuring agents in water (concentration: 0.5 mol/l) Solute Type T₂[ms] ± SEM [ms] — Water 129 20 Sucrose Structuring agent 18.7 0.1Sorbitol Structuring agent 119.4 14 Urea Destructuring 145 15 agentNicotinamide Destructuring 276 24 agent

The suitable ratio of the two substances was established in awide-ranging series of tests on testosterone and other steroid hormones.It emerged from this, surprisingly, that an additive increase in thetransdermal flux can be achieved if not only the structure of the wateris broken but, at the same time, more active substance is available fordissolving and diffusion through use of a solid dispersion of the activesubstance in the preparation.

A considerable improvement in the transdermal flux is surprisinglyachieved with the transdermal therapeutic system according to theinvention. The value for this in the cases investigated is at 1.4 timesthat for conventional TTS.

If accurate adjustment of the flux is desired for therapeuticrequirements, this can be achieved according to the invention bysimultaneous use of destructuring agents and structuring agents in anappropriate ratio.

Also provided is a composition according to the invention fortransdermal administration, which contains, in an amount of at leastmore than 10% by weight and less than 90% by weight, apenetration-enhancing agent of the following formula 1

in which R1 and R2 are identical or different and are selected from thegroup of C1- to C6-alkyl radicals, in particular the optionallybranched, saturated C1- to C4-alkyl radicals, R3 is selected from thegroup consisting of hydroxy-(C1- to C6-)alkyl radicals, in particularhydroxy-(C1- to C4-)alkyl radicals, and contains at least one activesubstance or its pharmaceutically acceptable salt and another lipophilicpenetration-enhancing agent.

Additionally provided according to the invention is another compositionfor transdermal administration. This comprises a penetration-enhancingagent of the formula 1 mentioned above, where R1, R2 and R3 are asdefined above, at least one active substance or its pharmaceuticallyacceptable salt and another lipophilic penetration-enhancing agent,excepting oleic acid, whose lipophilicity measured by determining thewater absorption capacity is in the region of 0-1.4% by weight,preferably in the region of 0.001-0.330% by weight or in the region of0.340-1.400% by weight.

The present invention thus relates to a composition for transdermaladministration comprising, in an amount of at least more than 10% byweight and less than 90% by weight, a penetration-enhancing agent of thefollowing formula 1

where R1 and R2 are identical or different and are selected from thegroup of C1- to C6-alkyl radicals, in particular the optionallybranched, saturated C1- to C4-alkyl radicals,

R3 is selected from the group consisting of hydroxy-(C1- to C6-)alkylradicals, in particular hydroxy-(C1- to C4-)alkyl radicals,

and at least one pharmaceutical active substance or its pharmaceuticallyacceptable salt and

another lipophilic penetration-enhancing agent.

The present invention also relates to a composition for transdermaladministration comprising a penetration-enhancing agent of the followingformula 1

where R1 and R2 are identical or different and are selected from thegroup of C1- to C6-alkyl radicals, in particular the optionallybranched, saturated C1- to C4-alkyl radicals,

R3 is selected from the group consisting of hydroxy-(C1- to C6-)alkylradicals, in particular hydroxy-(C1- to C4-)alkyl radicals,

and at least one pharmaceutical active substance or its pharmaceuticallyacceptable salt and

another lipophilic penetration-enhancing agent, excepting oleic acid,whose lipophilicity measured by determining the water absorptioncapacity is in the region of 0 to 1.4% by weight, preferably in theregion of 0.001 to 0.330% by weight or in the region of 0.340 to 1.400%by weight.

A preferred composition is one where the penetration-enhancing agent ofthe formula 1 is present in a content of more than 10 to 50% by weight,preferably more than 10 to 25% by weight, most preferably 15 to 25% byweight.

Also preferred is a composition where the penetration-enhancing agent ofthe formula 1 is Solketal (2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane).

A further preferred composition is one additionally containing a contactadhesive, preferably a contact adhesive based on mixtures containing(co)polymers based on constituents which are selected from the group ofC1- to C6-alkyl (meth)acrylates, C1- to C5-hydroxyalkyl (meth)acrylates,in particular containing a contact adhesive based on mixtures containing(co)polymers based on constituents selected from the group consisting ofvinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, glycidylmethacrylate, butyl acrylate, acrylic acid and methyl acrylate.

Additionally preferred is a composition where the other lipophilicpenetration-enhancing agent is selected from the group of saturatedhydrocarbons with 10 to 30 C atoms, of the optionally unsaturated fattyalcohols with 10 to 30 C atoms, of the saturated or unsaturated,monobasic or polybasic fatty acids with 8 to 30 C atoms and their esterswith optionally unsaturated fatty alcohols with 10 to 30 C atoms, andtriacylglycerides with fatty acid residues with 8 to 22 C atoms,preferably with 5 to 12 C atoms.

Particularly preferred in this connection is a composition where theother lipophilic penetration-enhancing agent is selected from the groupconsisting of dioctylcyclohexane, dodecanol, 2-octyldodecanol,2-hexyldodecanol, oleyl alcohol, lauric acid, oleic acid, palmitic acid,dioctyl ether, isopropyl myristate, hexyl laurate, cetearylisononanoate, capric acid, (C1- to C20-)alkyl caprates, (C1- toC20-)alkyl oleates, in particular decyl oleate, oleyl oleate, (C1- toC20-)alkyl docosenoates).

A very particularly preferred composition in this connection is onewhere the other lipophilic penetration-enhancing agent is ethyl oleate.

A further preferred composition is one where the other lipophilicpenetration-enhancing agent is present in a relative amount of at least2% by weight, preferably between 5 and 15% by weight.

A preferred composition is also one where another hydrophilicpenetration-enhancing agent which preferably has a solubility of atleast 5% by weight in water is present.

A particularly preferred composition in this connection is one where theother hydrophilic penetration-enhancing agent is selected from the groupconsisting of amides, polyethylene glycols, glycols, pyrrolidones,polymers of pyrrolidone derivatives, in particular nicotinamide or urea.

A very particularly preferred composition is one where the otherhydrophilic penetration-enhancing agent is present in a relative amountof from 1 to 10% by weight, preferably 2 to 5% by weight.

A further preferred composition is one where the active substance is alipophilic active substance, in particular a steroidal agent.

A particularly preferred composition in this connection is one where thesteroidal agent is a steroid hormone, in particular selected from thegroup consisting of cortico-steroids, sex hormones, preferablyoestrogens, gestagens, androgens, in particular from the groupconsisting of testosterone, estradiol and its derivatives, particularlypreferably testosterone, estradiol, ethinylestradiol and norethisteroneacetate.

An additionally preferred composition is one where the compositioncontains the active substance in at least saturated solution, preferablyin supersaturated solution.

The active substances present in the transdermal therapeutic systemaccording to the invention can be selected virtually as desired.Preferred active substances according to the invention are selected fromhormones, immunomodulators, immunosuppressants, antibiotics,cytostatics, diuretics, gastrointestinal agents, cardiovascular agentsand neuropharmaceuticals or mixtures thereof.

Hormones are particularly preferred, especially sex hormones such as,for example, testosterone, estradiol, estriol, norethisterone, dienogestor mixtures thereof.

The transdermal therapeutic systems according to the invention can beproduced by simple methods. These methods are essentially based onwell-known pharmaceutical technologies. The method avoids in principleall elaborate precision fabrication or special coating techniques. Themethod affords medicinal forms from which there is improved penetrationof hydrophilic medicinal substances through the skin.

The active substances are moreover used according to the invention inthe form of solid dispersions. Corresponding dispersions can beprepared, for example, as disclosed in DE-A 44 02 462.

The present invention furthermore relates to means for transdermaladministration comprising the composition according to the inventiondescribed above.

Particularly preferred in this connection is the means comprising anemulsion, ointment, cream, lotion or transdermal therapeutic system(TTS).

A particularly preferred TTS in this connection is one with anoptionally detachable protective layer (1), at least one contactadhesive matrix layer, in particular a contact adhesive-containingprimer layer (2), and a contact adhesive-containing cutaneous layer (3),another intermediate layer (4) and an optionally active substance-and/or water vapour-impermeable backing layer (5).

A particularly preferred TTS is one where the primer layer (2) and thecutaneous layer (3) project beyond the intermediate layer (4) on allsides.

Also preferred in this connection is a TTS where the composition ispresent where appropriate distributed in three compartments, namely thecontact adhesive-containing primer layer (2), the contactadhesive-containing cutaneous layer (3) and the other intermediate layer(4).

The matrix of the transdermal therapeutic system is according to theinvention a sheet-like adhesive material, a plaster, a patch, a gel, anointment, a cream, an emulsion, an embrocation, a paint or animpregnated fabric.

The present invention thus relates not only to the known sheet-likeadhesive materials (plasters, patches) but also to gels, ointments,creams, emulsions, embrocations, paints, impregnated.fabric and similaradministration devices of transdermal therapeutic systems as long asthey adhere to the skin or mucosa target organ.

The invention further relates to a method for producing the TTSaccording to the invention described above, comprising the steps of

producing a first laminate by a first mixture containing the at leastone active substance and an optionally cross-linkable contact adhesivebeing produced and applied to a protective layer (1) carrier material,

producing a second laminate by applying the first mixture to a backinglayer (5) carrier material,

a disc being punched out of another carrier material, preferably anonwoven, and being applied to the first laminate,

and a second mixture containing the penetration-enhancing agent offormula 1 and the other lipophilic penetration-enhancing agent beingapplied to the other carrier material,

the second laminate being laminated thereon and single TTS beingproduced therefrom.

The production of the TTS is otherwise based on the pharmaceuticaltechnology known in principle for these systems and thus can be carriedout in the pharmaceutical production facilities customary for thispurpose without special measures.

The invention finally relates to a product produced by this method foruse in replacement therapy, in particular hormone replacement therapy.

A preferred product in this connection is one for use for hypogonadism,anaemia, congenital angioneurotic oedema, impotence, infertility orcontraception.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the average serum concentrations of testosterone over aperiod of 48 hours in the test subjects (n=8). The serum concentrationsare in the range from 0.01 ng/ml after 1 hour to 1.25 ng/ml after 16hours.

FIG. 2 shows the average estradiol concentrations in the serum of thetest subjects (n=8) over a period of 24 hours. The serum concentrationsare in the range from 1.09 pg/ml after 0 hours up to 222.04 pg/ml after24 hours (estradiol cream 10 in each case).

FIG. 3 shows the average serum concentrations (n=8) of testosterone overa period of 34 hours. The serum concentrations are in the range from0.04 ng/ml after 1.5 hours to 2.20 ng/ml after 16 hours.

The invention is illustrated in detail by the following examples.

INVESTIGATION METHOD 1

The transdermal permeation of the appropriate medicinal substancesthrough excised cow udder skin (thickness 1.2 mm) was investigated in amodified FRANZ cell (Hansen-Research). At the start of the test, thevehicles used were introduced into the donor compartment of the cell,and the weight of active substance m permeated over a period of 56 h wasquantified by complete removal and replacement of the acceptorcompartment after t=8, 24, 32, 48 and 56 hours by UV or fluorescencespectroscopy detection and HPLC separation. The m/t profiles in the timesegment 24 h≦t≦56 h were linearized to calculate the in vitro flux Jfrom the gradient of the regression lines.

EXAMPLE 1

0.5% testosterone hydrogel

The following hydrogel was used:

Testosterone 0.500 g Carbopol ® 934 0.500 g Triethanolamine 0.500 gEthanol 96% 46.875 g Aqua purificata ad 100.000 g

The destructuring/structuring agents listed in Table 3 were added inappropriate concentration to the hydrogel, and the water content wasreduced by the appropriate weight.

The transdermal in vitro flux values J of the hydrogels, the standarddeviation S and the corresponding enhancement factors in the presence ofa destructuring/structuring agent are shown in Table 3.

TABLE 3 Flux J and enhancement factor F_(E) of the testosteronehydrogels with and without addition of destructuring/struc- turingagents Destructuring Structuring Flux J ± S agent agent Concentration[μg/cm²*h] F_(E) / / / 3.1 ± 1.1 Nicotinamide / 0.5 mol/kg 5.5 ± 1.21.75 Urea / 0.5 mol/kg 6.9 ± 2.3 2.22 / Lactose 45 g/kg 3.7 ± 0.7 1.19 /Lactose (solid 45 g/kg 7.4 ± 0.7 2.39 dispersion) Nicotinamide Lactose(solid 0.5 mol/kg/ 11.8 ± 2.4  3.8 dispersion) 45 g/kg

The flux J is found to be between 3.1±1.1 μg/cm²*h and 11.8±2.4μg/cm²*h. The enhancement factors on addition ofdestructuring/structuring agents are between 1.75 and 3.8. It was thuspossible to show that the in vitro flux of active substances can beincreased by adding destructuring agents and/or structuring agents insolid dispersions with the active substance. A combination of the two“enhancers” increases the flux additively.

EXAMPLE 2

4% estriol cream

The following cream was used:

Estriol 4.000 g Preservative 0.025 g Propylene glycol 2.000 g Siliconeoil 2.000 g Glycerol monostearate, self-emulsifying 5.000 gTriglycerides, medium chain length 5.000 g Lipid phase 35.200 g Purifiedwater 46.775 g

The destructuring/structuring agents listed in Table 4 were added inappropriate concentration to the hydrogel, and the water content wasreduced by the appropriate weight.

The transdermal in vitro flux values J of the creams, the standarddeviation S and the corresponding enhancement factors F_(E) in theabsence of a destructuring/structuring agent are shown in Table 4.

TABLE 4 Flux J and enhancement factor F_(E) of the estriol cream withand without addition of destructuring/structuring agents DestructuringStructuring Flux J ± S agent agent Concentration [μg/cm²*h] F_(E) / / /0.184 + 0.023 Nicotinamide / 1 mol/l 0.508 ± 0.060 2.76

The flux was found to be between 0.184±0.023 μg/cm²*h and 0.508±0.060μg/cm²*h. The enhancement factor on the addition of nicotinamide is2.76. It was thus possible to show that the in vitro flux of activesubstances can be increased by adding destructuring agents.

EXAMPLE 3

0.5% dienogest hydrogel

The following hydrogel was used:

Dienogest 0.500 g Carbopol ® 934 0.500 g Triethanolamine 0.500 g Ethanol96% 46.875 g Aqua purificata ad 100.000 g

The destructuring/structuring agents listed in Table 5 were added inappropriate concentration to the hydrogel, and the water content wasreduced by the appropriate weight.

The transdermal in vitro flux values J of the hydrogels, the standarddeviation S and the corresponding enhancement factors in the presence ofa destructuring/structuring agent are shown in Table 5.

TABLE 5 Flux J and enhancement factor F_(E) of the dienogest hydrogelswith and without addition of destructuring/structuring agentsDestructuring Structuring Flux J ± S agent agent Concentration[μg/cm²*h] F_(E) / / / 1.38 + 0.27 Nicotinamide lactose 0.5 mol/kg 1.97± 0.26 1.43 (solid 45 g/kg dispersion)

The flux J was found to be between 1.38±0.27 g/cm²*h and 1.97±0.26μg/cm²*h. The enhancement factors on addition ofdestructuring/structuring agents are 1.43. It was thus possible to showthat the in vitro flux of active substances can be increased by addingdestructuring agents and/or structuring agents in solid dispersions withthe active substance.

INVESTIGATIVE METHOD 2

Study Design

An open randomized three-arm cross-over study was carried out with onearm being the testosterone TTS. This TTS is intended to release 2.5 mgof testosterone in a controlled manner over 24 hours. The test subjectsselected were 9 postmenopausal or menopausal women from 20 to 65 yearsof age.

The testosterone TTS was applied at time t₀ to the forearm and removedafter 24 hours. The serum was taken at defined times and analysed forthe testosterone concentration by RIA. The last sample was taken 24hours after removal of the TTS.

EXAMPLE 4

The testosterone TTS investigated had the composition shown in Table 6.

TABLE 6 Composition of the testosterone TTS Raw material Content/TTS %in the matrix Testosterone 8.4 mg 3.00 Nicotinamide 14.0 mg 5.00 Matrix257.6 mg 92.00 Backing layer 35.0 cm² Release liner 46.2 cm²

The average testosterone serum concentrations with the testosterone TTSin the pilot study are compiled in Table 7.

TABLE 7 Testosterone serum concentrations c with the testosterone TTS asa function of the time t t [h] 1 2 3 4 5 7 8 10 c [ng/ml] 0.01 0.05 0.150.24 0.62 0.65 0.77 0.90 t [h] 12 16 24 25 26 28 32 48 c [ng/ml] 1.051.25 1.15 0.82 0.58 0.33 0.14 0.10

FIG. 1 shows the average serum concentrations of testosterone over aperiod of 48 hours in the test subjects (n=8). The serum concentrationsare in the range from 0.01 ng/ml after 1 hour to 1.25 ng/ml after 16hours.

After a short lag time of about 2 hours, there is seen to be a markedrise in the serum concentrations, which remains constant in the regionabove 1 ng/ml over 12 hours. 24 hours after application of the TTS, theserum level plot declines relatively abruptly. This means that afterabout 24 hours most of the testosterone has diffused out of the TTS andpermeated through the skin.

INVESTIGATIVE METHOD 3

Study Design

An open randomized three-arm cross-over study with “single dose”administration was carried out. The three arms were three estriol creamshaving the same base part differing in the dose of active substance. Theintention was to establish the bioavailability of estriol aftertransdermal administration. The test subjects selected were 9postmenopausal women. The appropriate estriol creams were applied attime t₀ to the forearm. The serum was taken at defined times in a periodup to 24 hours and analysed for the estriol concentration by RIA. Thelast sample was taken 24 hours after application of the creams.

EXAMPLE 5

Estriol Creams

The composition of the creams investigated is compiled in Table 8.

TABLE 8 Composition of estriol creams 1, 3 and 10 Active substances andauxiliaries Estriol 1 Estriol 3 Estriol 10 Estriol  1.000 g  3.000 g10.000 g Preservatives  0.025 g  0.024 g  0.022 g Propylene glycol 1.980 g  1.940 g  1.800 g Silicone oil  1.980 g  1.940 g  1.800 gGlycerol monostearate,  4.950 g  4.850 g  4.500 g self-emulsifyingTriglycerides, medium  4.950 g  4.850 g  4.500 g chain length Lipidphase 34.848 g 34.144 g 31.680 g Nicotinamide  6.039 g  5.917 g  5.490 gPurified water 44.228 g 43.335 g 40.208 g

FIG. 2 shows the average estriol concentrations in the serum of the testsubjects (n=8) over a period of 24 hours. The serum concentrations arein the range from 1.09 pg/ml after 0 hours up to 222.04 pg/ml after 24hours (estriol cream 10 in each case).

After a lag time of about 10-12 hours there is seen to be a marked risein the serum concentrations. They are highest with estriol cream 10 andlowest with estriol cream 1. There is an evident dependence of the serumconcentrations on the concentration and dose. Since the serumconcentrations continue to rise up to 24 hours after application withall three creams, a further rise in the serum concentrations is to beexpected.

INVESTIGATIVE METHOD 4

To examine the principle of action of the destructuring agents, NMRexperiments were carried out in a Bruker Biospec 47/40(Fraunhofer-Institut für Biomedizinische Technik, D-St. Ingbert). Thefield strength was 4.7 T. For reliability, three mutually adjacentcoronal slices were recorded simultaneously for the distal phalanx ofthe subject's middle finger in one experiment in each case (repetitiontime 1.5 s). 8 echo images were recorded with a time interval of 8 msfor the slice (Hermite pulses, duration 1 ms) to result in 24 images.The thickness of the selected slices was 2 mm. 256*256 pixels covering afield of 3 cm were recorded for each image. This ensured a resolution of120 μm in the plane of the image. The TOMIKON software was used foranalysis.

EXAMPLE 6

Hydrogel with 0.5 mol/kg nicotinamide

A gel with the inventive principle (cf. Example 1) was compared with agel without additions by application to the subjects (activesubstance-free gels were used for reasons connected with medicinalproduct legislation).

The investigation showed

1. from the proton spin density an effect on the water (probably inregion B) by the principle according to the invention,

2. from the T₂ relaxation times a distinct effect on the outer layers ofskin by the principle according to the invention.

A T₂ value of 46.4 ms was found in this in vitro study for an ethanolichydrogel without added nicotinamide. The addition of 1 M nicotinamideled to a T₂ value of 61.2 ms, whereas demonstration of the gel withadded nicotinamide using the HSP technique (solid dispersion of activesubstance and lactose) led to a shortening of the T₂ relaxation time of34.0 ms.

Summarizing, the result of the investigations can be summarized asfollows:

A destructuring agent makes free water available for dissolving anddiffusion. It is moreover possible to adjust the extent of this processby the nature and/or concentration of the destructuring agent and/or byadmixing a structuring agent very accurately to the requirements in eachcase.

The active substance can, if it is in the form of a solid dispersion,rapidly dissolve and diffuse in the free water.

INVESTIGATIVE METHOD 5

Study Design

An open randomized four-arm cross-over study was carried out with onearm being a testosterone TTS as in Example 7. This TTS is intended torelease 3.5 mg of testosterone in a controlled manner over 24 hours. Thetest subjects selected were 8 post- or menopausal women from 20 to 65years of age.

The testosterone TTS was applied at time t₀ to the forearm and removedafter 24 hours. Blood was taken from the women at defined times, and theserum testosterone concentration was analysed by RIA. The last bloodsample was taken 10 hours after removal of the TTS.

EXAMPLE 7

The investigated testosterone TTS had the composition shown in Table 9.

TABLE 9 Composition of the testosterone TTS Raw material Content/TTS %in the matrix Testosterone 21.0 mg 3.50 Nicotinamide 21.0 mg 3.50 Matrixcomponents 556.32 mg 93.00 Backing layer 35.0 cm² Release liner 46.2 cm²

The average serum testosterone concentrations the testosterone TTS arecompiled in Table 10.

TABLE 10 Serum testosterone concentrations c with the testosterone TTSas a function of time t t [h] 0 1.5 3 5 7 9 12 16 c [ng/ml] 0 0.04 0.400.78 1.40 1.57 1.88 2.20 t [h] 24 25 26 27 28 30 32 34 c [ng/ml] 2.0O1.29 1.21 0.98 0.86 0.76 0.43 0.24

FIG. 3 shows the average serum concentrations (n=8) of testosterone overa period of 34 hours. The serum concentrations are in the range from0.04 ng/ml after 1.5 hours to 2.20 ng/ml after 16 hours. After a shortlag time of about 2 hours, there is a marked increase in the serumconcentrations, which remains in the region above 1 ng/ml over 20 hours.24 hours after application of the TTS, the serum level plot shows acontinuous decline simultaneously with the removal of the TTS.

What is claimed is:
 1. Process for producing a transdermal therapeuticsystem comprising the steps of producing a first laminate containing amixture of at least one active substance and an optionallycross-linkable contact adhesive and applying the mixture to a protectivelayer carrier material; producing a second laminate by applying thefirst mixture to a backing layer carrier material; punching out a discof a second carrier material which is then applied to the firstlaminate; producing a second mixture containing a composition comprisinga penetration-enhancing agent in an amount of at least more than 10% byweight and less than 90% by weight, at least one pharmaceutically activesubstance or its pharmaceutically acceptable salt, and anotherlipophilic penetration-enhancing agent; applying this second mixtureonto said disc of the second carrier material; and laminating the firstand second laminates together and producing single transdermaltherapeutic systems therefrom.
 2. Process for producing a transdermaltherapeutic system comprising the steps of producing a first laminatecontaining a mixture of at least one active substance and an optionallycross-linkable contact adhesive and applying the mixture to a protectivelayer carrier material; producing a second laminate by applying thefirst mixture to a backing layer carrier material; punching out a discof a second carrier material which is then applied to the firstlaminate; producing a second mixture containing a composition comprisinga penetration-enhancing agent, at least one pharmaceutically activesubstance or its pharmaceutically acceptable salt, and anotherlipophilic penetration-enhancing agent whose lipophilicity measured bydetermining its water absorption capacity is between 0 and 1.4% byweight, with the proviso that the lipophilic penetration-enhancing agentis not oleic acid; applying this second mixture onto said disc of thesecond carrier material; and laminating the first and second laminatestogether and producing single transdermal therapeutic systems therefrom.3. The method of claim 1 wherein the penetration-enhancing agentcomprises formula (1)

wherein R₁ and R₂ are identical or different and are selected from thegroups of C₁- to C₆-alkyl radicals, and R₃ is selected from the groupconsisting of hydroxy-(C₁- to C₆-) alkyl radicals.
 4. The method ofclaim 2 wherein the penetration-enhancing agent comprises formula (1)

wherein R₁ and R₂ are identical or different and are selected from thegroups of C₁- to C₆-alkyl radicals, and R₃ is selected from the groupconsisting of hydroxy-(C₁- to C₆-) alkyl radicals.